Non-small-cell lung cancer: targeted therapies

Chemotherapy: is it still enough? The major progresses in understanding cancer biology and the mechanism of oncogenesis have allowed the development of several potential molecular target drugs for cancer treatment, which are components of signaling pathways or metabolic processes contributing to the acquisition of cancer phenotype. A general better tolerability, owing to a milder toxicity profi le than conventional chemotherapy, better target selectivity, availability for chronic treatment and, in some cases, oral administration, have marked these new targeted compounds as the most promising investigational drugs for cancer therapy. Several targeted agents have been extensively employed for the treatment of lung cancer, which remains the main killer. In fact, lung tumors are the leading cause of mortality due to cancer, with approximately 1.35 million new diagnoses and 1.18 million deaths worldwide in 2002 [1]. Lung cancer includes two main groups: non-small-cell lung cancer (NSCLC), which accounts for more than 80% and comprises squamous carcinoma, adenocarcinoma and un differentiated large-cell carcinoma, and small-cell lung cancer (SCLC) [2]. The majority of people diagnosed with NSCLC are unsuitable for surgery due to advanced disease, thus, palliation and patient quality-of-life are still the primary goal of therapy. Advanced disease represents the main fi eld in which the new targeted agents have been employed. Progresses with chemo therapeutic agents in advanced NSCLC seem to have reached a plateau [3], with a recent study showing that the combination of pemetrexed and cisplatin compared with gemcitabine plus cisplatin statistically improved the median survival time (MST) in patients with nonsquamous histology [4]. The outcome advantage of pemetrexed in nonsquamous histology was confi rmed by a retrospective analysis of a second-line trial involving pemetrexed versus docetaxel [5], and in a Phase III trial of platinum-based chemotherapy followed, or not, by pemetrexed maintenance [6]. This observation has its biological explanation in the higher protein level of thymydilate-synthase, the primary target of pemetrexed, observed in squamous cell carcinoma [7]. After this study, pemetrexed was licensed for use in the fi rst-line treatment of advanced nonsquamous NSCLC. Nevertheless, new treatment approaches are needed.